In humans, prostate cancer is one of the most commonly diagnosed malignancies in males and is the second leading cause of cancer related death in men. The American Cancer Society estimates that for the year 2000, 180,400 new cases of prostate cancer will be diagnosed with 31,900 deaths from the disease. In advanced stages, prostate cancer metastasizes to the bone. While advances in early diagnosis and treatment of locally confined tumors have been achieved, prostate cancer is incurable once it has metastasized. Patients with metastatic prostate cancer on hormonal therapy will eventually develop an androgen-refractory (androgen independent) state that will lead to disease progression and death. Currently, prostate-specific antigen (PSA) is the most widely used tumor marker for screening, diagnosis, and monitoring prostate cancer. However, widespread use of PSA as a tool for screening is controversial since PSA fails to discriminate accurately between benign and malignant prostate disease.
Depending on the stage of the cancer, prostate and bladder cancer treatment involves one or a combination of the following therapies: surgery to remove the cancerous tissue, radiation therapy, chemotherapy, androgen deprivation (e.g., hormonal therapy) in the case of prostate cancer. While surgical or radiation therapy significantly improves survival in patients with early stages of the disease, the therapeutic options are very limited for advanced cases, particularly for tumor recurrences following hormone ablation. The majority of patients who undergo hormone therapy progress to develop androgen-independent disease. Currently, there is no effective treatment for the 20-40% of prostate cancer patients who develop recurrent disease after surgery or radiation therapy, or for those in whom the cancer has metastasized at the time of diagnosis. Chemotherapy has its toxic side effects, especially in elderly patients. Development of new forms of therapy especially for disease refractory to androgen deprivation is an urgent need in the management of prostatic carcinoma.
The identification of a novel cell surface antigen, prostate stem cell antigen (PSCA) has been described, see, e.g., U.S. Pat. No. 5,856,136 (SCAH2), WO 99/14328 (protein PRO232), WO 98/40403 (PSCA), WO 98/51805 (PS116) and Reiter et al. Proc. Nat. Acad. Sci. 95:1735-1740 (1998). PSCA was initially cloned from a cDNA library of a LAPC-4 xenograft from a prostate cancer patient.
PSCA is a GPI-linked molecule of 123 amino acids that is expressed on the surface of a number of cell types including prostate and bladder tumor cells. The gene is located on the myc locus on 8Q24.2 which is a region amplified in 80% of prostate cancers. PSCA shows 30% homology with SCA-2. The protein has a hydrophobic signal sequence at the first 20 amino acids of the N-terminus and a GPI-anchoring sequence at amino acid 100-123 of the C-terminus (FIG. 2 on page 1737 of Reiter et al. (1998)). There are four predicted glycoslylation sites. The cell surface protein is shed with a t1/2 of about 10 hours in culture. It has been reported that PSCA is widely over-expressed across all stages of prostate cancer, including high grade prostatic intraepithelial neoplasia (PIN), and both androgen-dependent and -independent prostate tumors. Antibodies that are able to target PSCA-expressing tumor cells in vivo and that can internalize upon binding to the cells, have not been reported.
Antibody-based therapy has proved very effective in the treatment of various cancers. For example, HERCEPTIN® and RITUXAN® (both from Genentech, S. San Francisco), have been used successfully to treat breast cancer and non-Hodgkin's lymphoma, respectively. HERCEPTIN® is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) proto-oncogene. HER2 protein overexpression is observed in 25-30% of primary breast cancers. RITUXAN® is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Both these antibodies are produced in CHO cells.
The present invention provides alternative methods of treating cancer that overcome the limitations of conventional therapeutic methods as well as offer additional advantages that will be apparent from the detailed description below.